Self-antigens, in the form of differentiation antigens, are commonly recognized on melanoma and other cancers by the immune system. It has been unclear whether recognition of these antigens is relevant to immunity to cancer. The tyrosinase family has emerged as prototypes of differentiation antigens on human cancers. We actually do not know very much about immune recognition of these antigens, or other differentiation antigens. Recognition of these antigens presents many problems. First, how is recognition of these antigens possible in the face of immune tolerance. Second, even when recognition is possible, can this generate immunity that can reject cancer. Finally, if immunity to differentiation antigens can reject cancer, what are the potential autoimmune sequelae. We have used a mouse melanoma model to show that mice can be tolerant to tyrosinase family antigens. Tolerance can be broken by immunization wit altered forms of antigen. This can generate antibody and CD8+ T cell responses that are capable of rejecting tumors. CD4+ cells are required for immunity. Our aims are to: 1) Investigate how cancer immunity is uncoupled from autoimmunity; 2) Investigate the role of CD4+ T cell responses in tumor immunity against differentiation antigens.; and 3) Develop mouse models that develop endogenous invasive melanomas and study immunity against differentiation antigens at different steps in tumor progression.